New gem-difluoromethylene-containing isocyanide as a useful building block for the synthesis of difluorinated pseudopeptides via Ugi reaction

Article abstract of DOI:10.1016/j.tetlet.2009.02.056

A new and efficient method was developed for the synthesis of novel gem-difluoromethylene-containing isocyanide, which can be used as a building block for the synthesis of difluorinated pseudopeptides via Ugi reaction.

Full text of DOI:10.1016/j.tetlet.2009.02.056

Tetrahedron Letters 50 (2009) 1982–1985
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New gem-difluoromethylene-containing isocyanide as a useful building
block for the synthesis of difluorinated pseudopeptides via Ugi reaction
a
a
a
a
a
a,
*
Nianjin Liu a, Song Cao a,b, , Li Shen , Jingjing Wu , Jinlong Yu , Jian Zhang , Hui Li , Xuhong Qian
*
a Shanghai Key Laboratory of Chemical Biology, Center of Fluorine Chemical Technology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
b Key Laboratory of Organofluorine Chemistry, Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and efficient method was developed for the synthesis of novel gem-difluoromethylene-containing
isocyanide, which can be used as a building block for the synthesis of difluorinated pseudopeptides via
Ugi reaction.
Received 8 December 2008
Revised 8 February 2009
Accepted 10 February 2009
Available online 13 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Recently, fluorinated amino acids have received extensive
attention and played important roles in peptidomimetic and
medicinal chemistry.1 They exhibit interesting pharmacological ef-
fects and, therefore, are frequently used to construct various bio-
logically active peptides with enhanced enzymatic stability
compared with these non-fluorinated amino acids. Among them,
ery.7 However, up to now there were only a few reports on the
use of fluoro-containing building blocks as one of the components
in the multicomponent reactions.8 Therefore, the strategy we pro-
posed previously,9 multicomponent reactions including fluoro-
containing building blocks (MCRs-FBB), will be a powerful tool
for one-pot construction of complex and diverse fluoro-containing
molecules with high efficiency. Isocyanide is an extremely versatile
component in multicomponent reactions due to their exceptional
reactivity. The most unique character of isocyanide is that they
can react readily with both nucleophiles and electrophiles at the
same carbon atom to give expected or unexpected products. There-
fore, isocyanide-based multicomponent reactions have attracted
much attention as useful strategy for the discovery and develop-
ment of novel MCRs.10 In this Letter, firstly we synthesized a novel
a,a-difluoro-b-amino acids have been one of the most attractive
unusual amino acids.2 For example, (S)-methyl 3-acetamido-2,2-
difluoro-4-phenylbutanoate was found to be slow-binding or
reversible competitive inhibitors of
a-chymotrypsin, showing the
most potent inhibitory activity (Fig. 1).3 The replacement of the
methylene group with the difluoromethylene in b-amino acids
has been recognized as an important method in the blockage of
metabolic processes. The combination of fluorinated b-amino acid
moieties with naturally occurring pharmacophores can alter both
molecule metabolism and enzyme substrate recognition. For
example, the CH2 to CF2 transposition in the b-amino acid fragment
of Rhodopeptin, a natural cyclic tetrapeptide with antifungal activ-
ities, resulted in an improved toxicity profile.4
fluoro-containing building block,
a,a-difluoro-b-amino amide
bearing the isocyanide functionality, and then utilized the MCRs-
FBB strategy for the synthesis of several difluorinated pseudopep-
tides via Ugi reaction under solvent-free conditions.
3-Amino-N-cyclohexyl-2,2-difluoro-3-phenylpropanamide 6 is
the key intermediate for preparation of the novel difluorinated iso-
cyanide, N-cyclohexyl-2,2-difluoro-3-isocyano-3-phenylpropana-
mide 8. However, very few methods were reported for the
preparation of this kind of amide 6. Welch reported a method of
preparing this amide by using a new fluorinated building block,
1,1-difluoro-2-trimethylsilyl-2-trimethylsilyloxyethene, as start-
ing material.11 It is obvious that this method is not very practical
due to its unavailability. Although there are several reports on
the synthesis of 3-amino-2,2-difluoro-3-substituted propyl acid
and ester,12 the precursors of amide, there are several shortcom-
ings of these methods such as expensive starting materials,13 too
many steps.14 Here, we describe an efficient route to prepare 6
from commercially available fluoro-containing building block,
ethyl bromodifluoro acetate 1 (Scheme 1).
The general methods for introducing fluorine atoms into organ-
ic molecules involve either direct fluorination (using fluorine gas,
hydrogen fluoride, and fluorinating agents) or the use of fluori-
nated building blocks.5 The use of fluorinated building blocks as
a strategy for the construction of fluorinated organic molecules is
becoming more popular. Nowadays, fluorinated amino acids are
increasingly used as valuable building blocks for the incorporation
of fluorine into peptides and proteins.6 Despite their promising
applications in peptide chemistry, there are a very limited number
of versatile fluorinated amino acid building blocks to be used. Thus,
finding or designing efficient and practical fluorinated amino acid
building blocks seems to be important.
In recent years, multicomponent reactions have become one of
the most productive areas in organic synthesis and drug discov-
N-Benzylidene-4-methoxyaniline 2 was easily prepared in good
yield by condensation of benzaldehyde with 4-methoxyaniline in
methanol and used without further purification. 4-Methoxyaniline
* Corresponding authors. Tel.: +86 21 64253452; fax: +86 21 64252603 (S.C).
E-mail addresses: scao@ecust.edu.cn (S. Cao), xhqian@ecust.edu.cn (X. Qian).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.056

N. Liu et al. / Tetrahedron Letters 50 (2009) 1982–1985
1983
obtaining the key intermediate, 3-amino-N-cyclohexyl-2,2-di-
fluoro-3-phenylpropanamide 6, in 45% yield.
O
F
O
H
N
F
N
H
According to the related literatures, three strategies for the syn-
thesis of isocyanide 8 were tested. Initially, the reaction of 6 with
chloroform and 50% NaOH by using tetra-butylammonium bro-
mide as phase transfer catalyst at room temperature yielded little
product after a long reaction time (over 72 h). Although the reac-
tion proceeded smoothly in a much shorter time at elevated tem-
perature, unexpectedly, another isocyanide, N-cyclohexyl-2-
fluoro-3-isocyano-3-phenylacrylamide 9, was formed as the major
product, only 15% of the desired isocyanide 8 being obtained. The
structure of compound 9 was also identified by 1H, 13C, 19F NMR
and HRMS. In the second attempt, compound 7, N-cyclohexyl-
2,2-difluoro-3-formamido-3-phenylpropanamide, was successfully
prepared first by the treatment of 6 with ethyl formate. And then,
transformation of 7 to 8 under different reaction conditions was
investigated. Treatment of 7 with phosphorus oxychloride (POCl3)
in the presence of triethylamine (NEt3) gave a poor yield of 8. The
alternative approach to 8 by reaction of 7 with carbon tetrachloride
(CCl4) and triphenylphosphine (PPh3) in the presence of NEt3 in
refluxing dichloromethane proved unsuccessful. To accomplish
this task, other reaction conditions were screened including sol-
vent, time, and temperature. Finally, the reaction of 7 with CCl4,
NEt3, and PPh3 in a 1:2:2:2 ratio by using 1,2-dichloroethane as
solvent at 60 °C afforded the desired novel isocyanide 8 in 70%
yield.17
NH2
H
N
O
O
F
F
N
H
8
N
H
O
O
O
Figure 1. Difluorinated phenylalanine and Rhodopeptin.
was used as a nitrogen source, so as to have a substituent on the
nitrogen which makes its cleavage possible under mild conditions.
The reaction of Schiff base 2 with 1 in the presence of Zn dust in
THF via Reformatsky-type reaction afforded two products, diflu-
orinated b-aminoester 3 and b-lactam 4 in nearly 1:1 ratio in
excellent yield. It is easy to obtain amide 5 by the reaction of es-
ter 3 with cyclohexanamine. However, to the best of our knowl-
edge,
no
direct
aminolysis
from
3,3-difluoro-1-(4-
methoxyphenyl)-4-phenylazetidin-2-one 4 to the corresponding
amide 5 has been reported. The only method to aminolyze the
nonfluoro-substituted b-lactam was reported by Park in 1994
who used various amino acid esters to open b-lactam ring.15 In
2000, Ohta described the ring-opening reaction of difluorinated
b-lactam with sodium methoxide, followed by treatment with
primary amine (glycine tert-butyl ester hydrochloride) to give
aminolysis products.4 In order to improve reaction efficiency
and avoid the separation of the mixture of 3 and 4, herein, we
tried to obtain difluorinated amide 5 by the reaction of cyclohex-
anamine with the mixture of 3 and 4 directly. To our delight,
both of them could react with cyclohexanamine in methanol at
room temperature to afford the same product 5 in almost quan-
titative yield. The deprotection of 5 was effectively realized by
classical treatment with 3 equiv of ceric(IV) ammonium nitrate
(CAN) in a mixture of acetonitrile and water in a 9:1 ratio,16
Recently, we have reported a mild and efficient organic solvent-
free Ugi four-component condensation for the synthesis of pseudo-
peptides.18 In this Letter, after the successful synthesis of this novel
difluorinated isocyanide, we next wished to use this new fluorine-
containing building block to synthesize several difluorinated
pseudopeptides via Ugi reaction. Thus, 10a–d were obtained in
moderate to high yields at 60 °C under solvent-free conditions
for about 0.8 h (Scheme 2).19
O
NH2
O
F
C
A
B
N
N
H
HN
O
OC2H5
+
F
+
F
F
O
O
H
O
4
O
2
3
O
O
O
F
D
F
F
F
F
+
F
HN
O
N
H
H2N
N
H
CN
CN
N
H
F
F
O
N
H
6
5
8
minor
9 major
E
G
X
O
F
O
O
H
X
F
CN
N
H
H
N
H
N
H
I
F
F
8
7
Scheme 1. Synthesis of N-cyclohexyl-2,2-difluoro-3-isocyano-3-phenylpropanamide 8. Reagents and conditions: (A) CH3OH, reflux, 95%; (B) BrCF2COOEt 1, Zn, THF, reflux,
90%; (C) cyclohexanamine, CH3OH, rt, 95%; (D) CAN, CH3CN, H2O, 0 °C ? rt, 45%; (E) HCOOC2H5, rt, 95%; (F) 50% NaOH, CHCl3, Bu4NBr, rt or 50 °C, for 8, 15%, for 9, 53%; (G)
POCl3, NEt3, CH2Cl2; (H) PPh3, CCl4, NEt3, CH2Cl2, reflux; (I) PPh3, CCl4, NEt3, ClCH2CH2Cl, 60 °C, 70%.

1984
N. Liu et al. / Tetrahedron Letters 50 (2009) 1982–1985
O
O
O
F
H
N
H
N
F
N
O
O
O
CN
O
F
H
N
H
N
F
10a
N
O
O
O
F
H
N
F
O
CN
10b
O
O
O
O
F
8
H
N
H
N
F
N
O
O
O
F
H
H
N
F
N
10c
N
O
O
10d
Scheme 2. Several examples of a,a-difluoromethylene analogs of b-amino acid synthesized via Ugi reaction.
4. Nakayama, K.; Kawato, H. C.; Inagaki, H.; Nakajima, R.; Kitamura, A.; Someya,
K.; Ohta, T. Org. Lett. 2000, 2, 977–980.
In summary, we have developed an efficient method to synthe-
size novel gem-difluoromethylene-containing isocyanide, and then
utilized multicomponent reactions including fluoro-containing
building blocks (MCRs-FBB) strategy to prepare several difluorinat-
ed pseudopeptides via Ugi reaction under solvent-free conditions.
5. (a) Hagooly, A.; Sasson, R.; Rozen, S. J. Org. Chem. 2003, 68, 8279–8287; (b) Ren,
X.; Wan, W.; Jiang, H.; Hao, J. Mini-Rev. Org. Chem. 2007, 4, 330–337; (c) Yajima,
T.; Nagano, H. Org. Lett. 2007, 9, 2513–2515; (d) Wang, X.; Zhang, F.; Liu, J.
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Acknowledgments
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Sridharan, V.; Perumal, P. T.; Avendaño, C.; Menéndez, J. C. Tetrahedron 2007,
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Financial supports from the National High Technology Research
and
Development
Program
of
China
(863
Program,
2006AA10A201), the Shanghai Foundation of Science of Technol-
ogy (073919107), Shanghai Leading Academic Discipline Project
(B507), National Key Project for Basic Research (2003CB114405),
and the Shanghai Education Commission are kindly acknowledged.
Supplementary data
9. Shen, L.; Zhang, J.; Cao, S.; Yu, J.; Liu, N.; Wu, J.; Qian, X. Synlett 2008, 3058–
3062.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.056.
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3966–3974.
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16. Dondoni, A.; Massi, A.; Sabbatini, S. Chem. Eur. J. 2005, 11, 7110–7125.
17. Preparation of N-cyclohexyl-2,2-difluoro-3-isocyano-3-phenylpropanamide (8):
19. N-(1-(Benzo[d][1,3]dioxol-5-yl)-2-(3-(cyclohexylamino)-2,2-difluoro-3-oxo-1-
phenylpropylamino)-2-oxoethyl)-N-phenylbenzamide (10c): To a stirred aniline
(32 mg, 0.34 mmol), benzo[d][1,3]dioxole-5-carbaldehyde (51 mg, 0.34 mmol)
was added in portions for about 5 min. The mixture was stirred for 25 min
again at room temperature. Then, the reaction mixture was heated to 60 °C.
Benzoic acid (42 mg, 0.34 mmol) and 8 (100 mg, 0.34 mmol) were added in
portions for 10 min. Stirring was continued at 60 °C for 0.8 h (TLC). The
crude residue was purified by chromatography (AcOEt/heptane = 1:5) to give
the desired product 10c.Yield: 76%; white solid, mp: 221–223 °C. 1H NMR
(400 MHz, CDCl3): d 7.90 (d, J = 9.2 Hz, 1H), 7.41–7.11 (m, 10H), 7.06–7.05
(m, 3H), 6.97 (s, 2H), 6.82–6.79 (m, 2H), 6.69 (d, J = 7.6 Hz, 1H), 6.26 (s, 1H),
5.94 (s, 2H), 5.88 (d, J = 7.6 Hz, 1H), 5.82–5.74 (m, 1H), 3.66–3.58 (m, 1H),
1.60 (s, 5H), 1.32–0.83 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3): d 171.3,
N-Cyclohexyl-2,2-difluoro-3-formamido-3-phenylpropanamide
7
(1.55 g,
5 mmol), PPh3 (2.60 g, 10 mmol), CCl4 (1.54 g, 10 mmol), NEt3 (1.01 g,
10 mmol), and 1, 2-dichloroethane (15 mL) were added into a 50 mL round-
bottomed flask, and the mixture was stirred at 60 °C for about 2 h (GC–MS).
Then, the dark brown reaction mixture was cooled to room temperature.
Subsequently, white triethylamine hydrochloride salt was removed by
filtration and the solid was washed with CH2Cl2. The filtrate was
concentrated under reduced pressure and the resultant crude residue was
purified by chromatography (AcOEt/heptane = 1:8), and white isocyanide 8
was obtained. Yield, 70%; mp: 95–97 °C. IR (KBr, film): 3314, 2932, 2858, 2112,
1668, 1527, 1446, 1254 cmÀ1
;
1H NMR (400 MHz, CDCl3): d 7.49–7.36 (m, 5H),
169.3, 161.8 (t, JCF = 27.4 Hz), 147.7, 147.6, 141.1, 135.9, 135.8, 133.6, 130.2,
2
6.08 (s, 1H), 5.50 (t, JHF = 12.0 Hz, 1H), 3.80–3.71 (m, 1H), 1.96–0.93 (m, 10H)
129.5, 128.8, 128.7, 128.6, 128.5, 127.7, 127.6, 127.3, 124.1, 117.3 (dd,
2
2
ppm; 13C NMR (100 MHz, DMSO-d6): d 161.3, 159.8 (t, JCF = 26.7 Hz), 130.3,
1JCF = 258.0, 274.8 Hz), 110.5, 108.1, 101.2, 66.3, 56.3 (dd, JCF = 24.8,
1
2
129.3, 128.9, 128.7, 113.7 (dd, JCF = 260.8, 260.5 Hz), 59.6 (dd, JCF = 24.1,
25.8 Hz), 49.0, 32.0, 31.8, 25.4, 25.2, 25.1 ppm; 19F NMR (470 MHz, CDCl3): d
À110.0 (dd, J = 9.5, 256.5 Hz, 1F), À114.1 ppm (dd, J = 9.5, 256.5 Hz, 1F); HRMS
(ESI): m/z: 293.1468 [M+H]+; calcd for C16H18F2N2O + H: 293.1465.
27.1 Hz), 48.3, 32.2, 25.2, 24.5, 24.4 ppm; 19F NMR (470 MHz, CDCl3):
d
À111.6, À112.1 (d, J = 4.8 Hz), À113.0 (d, J = 9.5 Hz), À113.5 (d, J = 9.5 Hz)
ppm; HRMS (ESI): m/z: 662.2424 [M+Na]+; calcd for C37H35F2N3O5+Na:
662.2442.